Angiogenesis refers to the growth of new blood vessels, either through sprouting or vessel splitting. It is a condition which exists in health on three occasions: menstruation, pregnancy and wound healing (when capillaries rush to a wound site to heal it and retreat after approximately 10-14 days). However, pathological angiogenesis, the abnormal and rapid development of blood vessels, is associated with and drives many diseases including cancer, psoriasis and age-related macular degeneration. In cancerous tissue, tumors cannot grow or spread (metastasize) without the development of new blood vessels. Blood vessels supply tissues with oxygen and nutrients necessary for survival and growth. Endothelial cells, the cells that form the walls of blood vessels, are the source of new blood vessels.
New vessel growth is tightly controlled by a finely tuned balance between factors that activate endothelial cell growth and those that inhibit it. Over 50 individual endogenous angiogenic regulators have been identified as angiogenic factors. They may be measured in blood, serum, urine, tissue and lymph samples. Regulators are broadly classified as: 1) angiogenic activators, stimulators, or growth factors; and 2) endogenous angiogenic inhibitors (cf. synthetic drugs intended to inhibit angiogenesis). It is the unique relationship between these two types of regulators that determines if angiogenesis occurs and thereby supports disease.
For example, about 50 proteins are currently known to regulate endothelial cell replication, some of which are shown in Table I.
TABLE INAMEFULL NAMEVEG-FVascular Endothelial Growth FactorEGFEpidermal Growth FactorbFGF-BasicFibroblast Growth Factor-BasicIL-2Interleukin-2PDGF-BBPlatelet-derived Growth Factor-BBTNF-αTumor Necrosis Factor-alphaIL-1βInterleukin-1 betaIL-8Interleukin-8IL-10Interleukin-10TSP-1Thrombospondin-1COX-2CyclooxygenaceHGFHepatocyte Growth FactorIGF-1Insulin like Growth FactorMMP-2Matrix Metalloproteinase-2MMP-9Matrix Metalloproteinase-9TNF-βTumor Necrosis Factor-betaTGF-βTransforming Growth Factor-betaAngiogeninAngiogeninGM-CSFGranulocyte Macrophage Colony-Stimulating FactorEndostatinEndostatin (collagen XVIII fragment)AngiostatinAngiostatin (plasminogen fragment)IL-6Interleukin-6G-CSFGranulocyte Colony-Stimulating FactorIL-7Interleukin-7Kringle 5Kringle 5 (plasminogen fragment)Angiopoitin-1Angiopoitin-1FGA/FGBFibrinogin
At a critical point in the growth of a tumor, the tumor sends out signals to the nearby capillaries to activate new blood vessel growth. Two endothelial growth factors, VEGF and bFGF, are expressed by many tumors and seem to be among the most important angiogenic stimulators in sustaining tumor growth. The role of angiogenic inhibitors is to keep angiogenic stimulators within their normal range. Inhibitors have half lives which are measured in hours and days, while stimulators' half lives are considerably shorter, most measured in only minutes.
Although first discovered in the late 1960's at Harvard by Dr. Judah Folkman, angiogenesis as a field of knowledge and discovery is still largely dominated by research scientists. Although many physicians and some patients have heard the term angiogenesis, few understand the role of angiogenesis in cancer and numerous other diseases. Peer-reviewed literature documenting the role of angiogenesis in disease and in reversing disease, unless directly tied to an angiogenesis inhibiting pharmaceutical, is customarily not read by most clinicians.
While studies documenting the beneficial effects of less than a dozen angiogenesis inhibiting pharmaceuticals increase in number annually, during the last several decades many peer-reviewed studies have been published which demonstrate how beneficially moderating individual angiogenic inhibitors, through the utilization of natural compounds and other techniques, suppresses disease stimulating angiogenic growth factors. These studies are largely unknown to the practicing medical community. Studies have shown such natural compounds to be safe and effective in the treatment of disease, cost effective, and almost entirely without side effects, and yet most physicians have no knowledge of their well-documented benefit in treatment of disease.
It is estimated that the amount of published literature with respect to the various aspects of medicine, angiogenesis and the diseases it drives doubles every five years. Based solely on the volume of literature, the most advanced treatment options are not always known by practicing clinicians.
For a physician or patient to perform a literature search on the basis of a specific patient sample analysis to determine the full range of peer-reviewed medical articles providing relevant information with respect to the multitude of angiogenic regulators would consume days if not weeks of extensive research. To date, it has not been known to couple the results of an angiogenic diagnostic test with specific peer-reviewed studies providing a range of treatment options to thereby stimulate therapy discussions between physician and patient.